Dementia is a loss of cognitive function that is extremely costly to individuals and society. Dementia is not defined by a single cause or pathology, and is most often attributed to Alzheimer's disease (AD, ~70%) and vascular dementia (VaD, ~17%), yet a considerable number of dementia cases (20-50%) share aspects of both. The broad objective of this proposal is to improve characterization of the commonalities and differences between these forms of dementia. Better understanding can improve diagnosis of dementias within this spectrum, interpretation of clinical results confounded by co-morbidity, and direction of therapeutic approaches. In order to better understand the overlap and differences between dementias within the spectrum between AD and VaD, this proposal focuses on two factors often shared between AD and VaD, hyperhomocysteinemia (HHcy) and tau pathology. HHcy is a risk factor for cardiovascular disease and related VaD, but is also frequently present in AD and other dementias. HHcy may play a causal role in the development of dementia. Tau pathology is a hallmark of AD, but is also present in a range of neurodegenerative diseases, including VaD, and may be promoted by HHcy. The focused objectives of this proposal are to understand the interactions between cerebrovascular and tau pathologies, identify mechanism by which HHcy may promote tau pathology and to address interventional approaches that may be useful in dementia patients with HHcy. In order to address these objectives, this proposal will utilize a model of diet-induced chronic HHcy developed by our lab and a recently developed transgenic mouse that expresses a suppressible human tau transgene. Aim 1 will evaluate the interactions between HHcy and tau, particularly the effects on cognitive deficit, and address dietary reversal of HHcy and pharmacological suppression of tau pathology as therapeutic approaches. Aim 2 will determine if changes in the metabolic pathway of homocysteine are likely pathway for an HHcy-induced increase in tau pathology. HHcy-induced vascular pathology (microhemorrhage), tau pathology (oligomers, hyperphosphorylated species and neurofibrillary tangles), cognitive impairment (spatial memory) and enzymes/metabolites of homocysteine metabolism will be evaluated. These aims investigate separate aspects of the relationship between HHcy, tau and cognitive impairment. Each aim will offer valuable information to determine the usefulness of intervention strategies to reduce HHcy and tau pathology in the substantial subset of dementia patients with comorbid HHcy. Finally, these studies provide the opportunity to broaden my repertoire of technical skills and develop intellectually under the mentorship of my sponsor and mentoring committee. In particular I will learn: magnetic resonance imaging in mice, use of transgenic mice, assessment of tau and vascular pathology, and how to address a need with the development of a novel model. These aims are designed to support my gradual progression toward autonomy and will provide the foundation for independent research.